(1) The trace element vanadium can act like insulin, a major regulator of lipid metabolism. We demonstrated that in vitro, vanadium at concentrations as low as 250 nM significantly reduces synthesis of the major atherogenic protein apolipoprotein B-100 in Caco-2 cells (an intestinal human cell line). In addition, another form of apoB, apoB-48, considered nonatherogenic, is increased by vanadium. Vanadium is known to be a nonspecific phosphatase inhibitor. To further evaluate the molecular mechanism, various specific kinase activators andphophatase inhibitors are being evaluated. In a pilot in vivo study, a rabbit model of familial hypercholesterolemia (Watanabe breed) with elevated cholesterol, triglycerides and atherosclerosis was fed vanadate. A reductionwas seen in cholesterol, triglyceride, and apolipoprotein B as well as an increase in HDL cholesterol, the so called "good cholesterol." A followup study with 10 rabbits as well as rats will be done to further delineate thephysiologic effects of vanadium. (2) We have begun a study has begun evaluating the effect of niacin, a lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a) in patients with systemic lupus erythematosus (SLE); another study is evaluating thyroid hormone induced changes in Lp(a) in thyroid cancer patients. During treatment for thyroid cancer, thyroid hormone levels are iatrogenically varied, allowing the effect of high and low levels of thyroid hormone on Lp(a) to be determined. We have begun a trial in these patients to examine the effect of niacin, anotherlipid lowering drug, on the markedly atherogenic lipoprotein Lp(a). A collaborative study involves determining lipid effects of IL-6 was done in normal individuals. A single dose of IL-6 reduced cholesterol, trigylcerides and apolipoprotein B, Lp(a) did not change. (3) We are also developing transgenic and knockout REPR mice using a new methodology--RNA/DNA hybrids. With this procedure the RNA targets the hybrid to a specific region in the genome, the DNA portion is thought to then induce a repair process to modify a single targeted base, resulting in the desired change within the genome. The method has been used to induce a single base change in cultured cells. We are now attempting to utilize mouse embryonic stem cells and are injecting the RNA/DNA hybrids into mouse oocytes to create new animal models.